Estrogen plays a pivotal role in the proper development and physiological function of both female and male reproductive organs. Environmental chemicals that interfere with the estrogen functions could cause various cellular abnormalities, thus endanger our health. In order to address the question on how environmental factors interfere with estrogen's function, we need to understand the intricate molecular event associated with gene expression under the influence of estrogen. With molecular approach, ER-mediated transactivation through the estrogen response element of lactoferrin gene has been studied. An estrogen-related receptor alpha (ERRa) binding element (ERRE) of the lactoferrin gene was found important in estrogen responsiveness. The ERRa modulates estrogen response either positively or negatively by competing for the same response element and coactivators of the ERs. Recent evidence demonstrate that ERRa up- regulates sets of genes involved in mitochondria oxidative phosphorylation and mitochondria biogenesis when the demand for energy production is increased. Additionally, ERRa regulates the expression of monoamine oxidase (MAOs) gene and epithelial nitro oxide synthase (eNOS) gene which participates in neurotransmitter degradation and in NO production in epithelial cells, respectively. To understand the in vivo function of ERRa, generating ERRa-null (ERRa KO) or tissue specific ERRa-null mouse will be useful especially since the receptor is active without ligand. We have designed the construct to produce the ERRa KO and ERRa floxed mouse. At the present time, positive recombinant chimera ES cells are being introduced into the female mouse. Since ERRa is constitutively active, regulation of its expression could be important in its biological roles. We found that estrogen stimulates ERRa gene expression in mouse uterus and a 34bp DNA element contains multiple steroid hormone response element half-sites (MHREs) of the gene is responsible for the estrogen stimulation. The MHREs also mediates the inducible peroxisome proliferators-activated receptor g coactivator-1a (PGC-1a) and estrogen related receptor g (ERRg) stimulation. These studies demonstrated a complicated regulation of ERRa gene expression through a common MHREs. Currently, we have mapped the nucleosome position of the ERRa gene at the MHREs region and modification of the nucleosome at this region under different signaling pathways will be examined.